Methylphenidate was first prepared as a mixture of the erythro [R*S*] and threo [R*R*] racemates. U.S. Pat. No. 2,957,880 discloses studies upon the two racemic mixtures, which revealed that the therapeutic activity resides in the threo diastereoisomer. It is now considered that it is the d-threo [or (R,R)] enantiomer that has the preferred therapeutic activity. Uses of this enantiomer are disclosed in PCT/GB96/01688 (International Publication No. WO 97/03671), PCT/GB96/01689 (International Publication No. WO 97/03672) and PCT/GB96/01690 (International Publication No. WO 97/03673), the contents of which are incorporated herein by reference.
The resolution of threo-methylphenidate can be achieved using the expensive resolving agent 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate, a process first reported by Patrick et al, The Journal of Pharmacology and Experimental Therapeutics, 241:152–158 (1987). A more efficient resolution, using a O,O′-diaroyltartaric acid, is disclosed in PCT/GE97/00185, the contents of which are incorporated by reference: in particular, the use of O,O′-di-p-toluoyltartaric acid allows the diastereoisomeric salts to be very readily separated.
In an alternative approach, disclosed in U.S. Pat. No. 2,957,880, the amide of erythro-methylphenidate (i.e. as -CONH2 instead of -CO2Me) is resolved using tartaric acid. However, this resolution must be followed by amide hydrolysis, and equilibration at the benzylic centre, to give the threo isomer of the carboxylic acid (ritalinic acid) which is esterified. U.S. Pat. No. 2,957,880 describes a general process for conversion of erythro diastereoisomers to threo diastereoisomers, using alkali and elevated temperature.
In order to establish an economic resolution process, it is highly desirable to be able to recycle the unwanted enantiomer into the resolution by way of a racemisation. This becomes especially important when the resolution is performed late in a synthesis. An example of such a resolution and racemisation procedure is in the case of naproxen where the single sterogenic carbon centre, which is benzylic and further activated by the carboxylate, is readily racemised. However, in the case of methylphenidate, there are two stereogenic centres. While one centre is similarly benzylic and can be epimerised as indicated in U.S. Pat. No. 2,957,880, that converts the material into a mixture of two diastereoisomers and not into the racemate that is required for recycling.